The aim of the present invention was to provide a novel bone cement, based on poly(methyl methacrylate) (PMMA), copolymers, and analogous systems which cure by radical polymerization, containing additives that cause the cement surface to mineralize upon incubation in simulated body fluid, and in which the mineralization layers obtained contain calcium phosphate phases such that the formation of fibrous intermediate layers is prevented once the bone cement has been implanted in bone.
Polymer-based bone cements are well known and are used, for example, in orthopedics, trauma surgery, and/or spine surgery, as well as in oral and maxillofacial surgery, for the filling and bridging of bone defects and for the fixation of implants. Their advantage over other standard materials such as e.g. metal implants, mineral bone cements based on calcium phosphates, calcium phosphate-based bone substitute materials, and alternative treatment options is that they are easy to handle, rapidly attain final strength (10-30 min.), have high fatigue strength and stability, are relatively well tolerated (sufficient biocompatibility), are freely moldable, and are in general a comparatively cost-efficient application in many fields concerned with bone surgery. Although these high quality materials have been in clinical use for more than 40 years, only few innovative approaches in the field of polymer-based bone cements have been introduced into clinical practice in recent years. As examples for current research approaches, the following directions of work shall be mentioned:                Improvement in handling by substituting powder-liquid mixing systems with 2-paste systems,                    Belkoff et al; Biomechanical Evaluation of a New Bone Cement for Use in Vertebroplasty. Spine. 25(9): 1061-64, May 1, 2000.                        reinforcement through fiber addition,                    Saha S.; Pal S. Improvement of mechanical properties of acrylic bone cement by fibre reinforcement. J. Biomech. 17:467-478. 1984;            Gilbert et al. Self-Reinforced composite poly(methyl methacrylate): Static and fatigue properties. Biomaterials. 16:1043-1055. 1955.                        alternative x-ray contrast media                    Van Hooy-Corstjens et al. Mechanical behavior of a new acrylic radiopaque iodine-containing bone cement. Biomaterials, 25, 2657-2667, (2004);            Kjellsson et al. Tensile properties of a bone cement containing non-ionic contrast media. J Mater Sci Mater Med. 2001 October-December: 12 (10-12):889-94                        addition of various filler and carrier substances,                    Liebendörfer et al. Experimental studies on a new bone cement: Hydroxyapatite composite resin. The 21st Annual Meeting of the Society for Biomaterials. San Francisco. USA, 335. 1995.            Shinzato et al.: Bioactive bone cement: Effect of phosphoric ester monomer on mechanical properties and osteo-conductivity in J. Biomed. Mater. Res. 2001; 56(4); 571-577.            Miyazaki et al.: Bioactive PMMA bone cement prepared by modification with methacryloxypropyltrimethoxysilane and calcium chloride. J. Biomed. Mater. Res. 2003; 67A(4); 1417-1423.            Fujita et al.: Bioactive bone cement: Effect of the amount of glass-ceramic powder on bone bonding strength. J Biomed Mater Res. 1998 April; (1):145-52                        
Published approaches concerned with the bioactivation of bone cements are based exclusively on the addition of bioactive substances to the polymeric matrix, mostly using very high filling levels (composite cements). In contrast, the aspects of biocompatibility and bioactivity/osteoconductivity of conventional polymer-based bone cements have so far scarcely received attention and even if the products applied to date are, in fact, basically biocompatible and do not generate any pronounced foreign body reactions, they still have the great and distinct disadvantage that they are not sufficiently bioactive to enable direct bonding with bone, that is intergrowth with the same. Osteoconductivity is given, by definition, only when bone is able to actively incorporate the implanted material and directly grows on its surface without creation of a fibrous intermediate layer or is able to cover the same without formation of an intervening gap. These fibrous intermediate layers are formed in the case of all hitherto known polymer-based (conventional) bone cements due to insufficient integration. The fibrous or connective tissue-like intermediate layer can also be seen as a scar tissue with which the body segregates itself from the environment or from a foreign body after an injury. Such layer systems, bone—fibrous intermediate layer—implanted material, have the great disadvantage that they are mechanically unstable, thus causing micromovements which eventually may lead to rejection of the implant, i.e. to so-called implant failure.
Therefore the success of implantations, when polymer-based bone cements are used, strongly depends on a close interlocking of the cancellous bone and the paste-like cement dough during implantation. It is precisely this necessity that sets a considerable limitation to the application field of polymer-based bone cements. This disadvantage is all the more significant, in view of the many alternative and competing implant materials that have meanwhile been equipped with osteoconductive surfaces, e.g. metal implants with bioactive coatings, bone mineral cements based on calcium phosphates, calcium phosphate-based bone substitute materials.
Distinctions from Prior Art:
The patent search on bioactive PMMA cements (PMMA=poly(methyl methacrylate) delivered no search hits or references. Bioactive PMMA cements are described in the literature exclusively as composites comprising a PMMA cement and filling substances made of bioactive glass or hydroxyapatite.
Of particular interest in this context is the publication of Shinzato et al.: Bioactive bone cement: Effect of phosphoric ester monomer on mechanical properties and osteoconductivity in J. Biomed. Mater. Res. 2001; 56(4); 571-577. As distinguished from the present invention (described further below), the phosphoric ester monomer, in this example of Shinzato, is also not added to a classical PMMA cement, but is added as an adhesion promoting agent to a PMMA-Bioglass composite cement. The effect on the mechanical properties and bioactivity has been described as positive. The authors interpret the found results as being the effect of the decreased polymerization tendency of the phosphoric ester monomer (PE) as compared to MMA (MMA=methylacrylate), which ultimately leads to an enrichment or stronger exposition of the bioactive glass particles at the cement surface. This publication contains no reference regarding the bioactive property of the PE monomer and other monomers according to the invention in classical PMMA cements. The bioactive effect is exclusively attributed to the bioactive glass particles.
The work of Miyazaki et al.: Bioactive PMMA bone cement prepared by modification with methacryloxypropyltrimethoxysilane and calcium chloride (J. Biomed. Mater. Res. 2003; 67A(4); 1417-1423), describes the formation of apatite on appropriately modified cements after incubation in SBF (SBF=simulated body fluid). However, the concentrations said to be necessary are so high that both setting behavior as well as the mechanical properties of the resulting cement are deteriorated considerably.
Neither publication anticipates the experimental results we obtained in the context of the present invention, nor do they suggest the same, particularly, as in the work of Shinzato, bioactivity is ascribed to the addition of bioactive glass at approximately 70 wt %. In the work of Miyazaki, apatite formation on the cement surface is only established after addition of more than 16% CaCl2. In contrast, in our experiments related to the present invention, the desired bioactive effect has been found and verified even after adding only a small amount of a monomer according to the invention such as e.g. methacrylic acid, or ethyleneglycol methacrylate phosphate, at a percentage under 10 weight percent, however, preferably under 5 weight percent and, in particular, under 3 weight percent, without addition of CaCl2. According to our invention aimed at providing an improved bioactive bone cement, the primary effect lies in the formation of crystallization seeds supported by the spontaneous release of calcium ions from the soluble calcium salts added to the bone cement and the short term increase in the local pH value to neutral and slightly basic values. This surprising and also unexpected effect has not been observed in any of the hitherto known bone cements or specifically polymer-based bone cements.
Cortoss®, a product of Orthovita, is currently the sole known polymer-based bone cement on the market that claims to be bioactive. This is a composite material comprised of a curing polymeric matrix with a high filler content of particulate Bioglass. Wherever the bioactive glass particles are present on the surface of the cement, the bioactivity of the Bioglass takes effect. The polymeric matrix itself, even in this case, is not bioactive, in contrast to the present invention. The essentially high proportion of bioactive filler material of up to 70 wt % in said cement—as well as in some known experimental composites from other sources (see above)—is coupled with considerable disadvantages with respect to cement properties that are relevant to and indispensable for a range of notable clinical indications. Of great consequence are changes in the mechanical data and in this case, in particular, the greatly increased stiffness (elastic modulus) together with decreased flexural strength. Due to this brittleness, Cortoss® is unsuitable for the fixation of joint implants. Further disadvantages are that these types of cements have to be designed as 2-paste systems, since the solid und liquid components cannot be mixed in the conventional manner. To be noted, in particular, are the resulting problems such as the sedimentation of the Bioglass filler material and the continuous premature degradation of the radical starter before the curing reaction (during storage). Both problems considerably limit shelflife and necessitate permanent storage in a refrigerator. In said cement, the utilized macromer curing systems are based on the polymer component Bisphenol A (Bis-GMA=bisphenol A glycidyl methacrylate), which is potentially more toxic than the conventional methyl methacrylate. A further great disadvantage of such cements based on novel polymer compositions (in the application as implant material) is the lack of long-term experience compared to the products used from the group of conventional PMMA bone cements which, however, are all not bioactive.
The objective and aim of the present invention therefore, is to find a way to achieve a bioactive/osteoconductive cement surface that develops not only rapidly, but also permanently after or during mixing and implantation, thereby retaining the other relevant properties of the source cement without unfavorably influencing the same, as previously described in the case of Cortoss®. It is familiar to those skilled in the art that the amount of components added to achieve bioactivity should be small. Thus the adopted research approach was contradistinctive to such 2-paste cement systems like Cortoss®, which for the purpose of bioactivity is modified in such a way that with the help of very high filler contents a sufficiently high amount of bioactive particles is presented at the implant surface.
A well-known principle for surface bioactivation of materials in bone contact is the creation of calcium phosphate phases on the material surface through coating or other processes, especially in the case of metals (HA plasma spraying or electrochemically deposited coatings—BoneMaster).                Mineralization of gelatine, R. Kniep, S. Busch, Angew. Chem., 1996, 108, 2788        Mineralization of collagen, S. Rössler et al. Mineralised collagen coating as a biomimetic approach to implant surfaces. Biomaterials 2004.        Kokubo et al. Apatite formation on non-woven fabric of carboxymethylated chitin in SBF. Biomaterials, 2003.        Kawai et al. Coating of an apatite layer on polyamide films containing sulfonic groups by a biomimetic process. Biomaterials, 2003        
However, what has always been disadvantageous for the known synthetic polymers concerning feasibility in their use in technical/medical applications—as far as they are at all suitable as implant material—is that they either have to be pretreated chemically so as to obtain acidic groups on the surface that function as crystallization seeds, and/or it is necessary to include calcium salts, as in the example of Miyazaki et al., in which apatite formation on the cement surface could only be achieved after addition of more than 16% CaCl2. With these modifications, to a greater or lesser extent, the synthetic polymers also demonstrated a good mineralization with calcium phosphate phases after incubation in simulated body fluid such as e.g. SBF (simulated body fluid, recipe see below), which would suggest that the respective mineral phases are also created in vivo after implantation.
Cement-like, polymer-based preparations that are potentially capable of surface mineralization in SBF are hitherto unknown in the literature, the reason being, apparently, that the known approaches are not practicable in cements, because in contrast to prefabricated implants, the surface of a cement is developed only in the course of the mixing process or during or after introduction into the body. It is absolutely imperative and a basic principle of the present invention that approaches to bioactivate cement surfaces therefore, must also take effect on the surface in the course of the cement curing process in said manner. The actual mineralization process may preferably then follow in vivo which, however, should commence as rapidly as possible so that adjacent bone cells are offered an attractive environment for adhesion in the early phase soon after implantation.